The V-ATPase–ATG16L1 axis recruits LRRK2 to facilitate the lysosomal stress response

Author:

Eguchi Tomoya12ORCID,Sakurai Maria1ORCID,Wang Yingxue3ORCID,Saito Chieko2ORCID,Yoshii Gen1ORCID,Wileman Thomas3ORCID,Mizushima Noboru2ORCID,Kuwahara Tomoki1ORCID,Iwatsubo Takeshi1ORCID

Affiliation:

1. Graduate School of Medicine, The University of Tokyo 1 Department of Neuropathology, , Tokyo, Japan

2. Graduate School of Medicine, The University of Tokyo 2 Department of Biochemistry and Molecular Biology, , Tokyo, Japan

3. Norwich Medical School, University of East Anglia 3 , Norwich, UK

Abstract

Leucine-rich repeat kinase 2 (LRRK2), a Rab kinase associated with Parkinson’s disease and several inflammatory diseases, has been shown to localize to stressed lysosomes and get activated to regulate lysosomal homeostasis. However, the mechanisms of LRRK2 recruitment and activation have not been well understood. Here, we found that the ATG8 conjugation system regulates the recruitment of LRRK2 as well as LC3 onto single membranes of stressed lysosomes/phagosomes. This recruitment did not require FIP200-containing autophagy initiation complex, nor did it occur on double-membrane autophagosomes, suggesting independence from canonical autophagy. Consistently, LRRK2 recruitment was regulated by the V-ATPase–ATG16L1 axis, which requires the WD40 domain of ATG16L1 and specifically mediates ATG8 lipidation on single membranes. This mechanism was also responsible for the lysosomal stress-induced activation of LRRK2 and the resultant regulation of lysosomal secretion and enlargement. These results indicate that the V-ATPase–ATG16L1 axis serves a novel non-autophagic role in the maintenance of lysosomal homeostasis by recruiting LRRK2.

Funder

Japan Society for the Promotion of Science KAKENHI

University of Tokyo

Exploratory Research for Advanced Technology

Japan Science and Technology Agency

Biotechnology and Biological Sciences Research Council

Publisher

Rockefeller University Press

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